Genome-editing medicines – a shifting regulatory landscape

by | Jun 21, 2024 | European Medicines Agency, Regulatory Affairs


  • Overview of recent Casgevy EMA approval
  • World Health Organisation’s (WHO’s) governance framework
  • EMA’s perspective on genome editing medicines


Genome-editing medicines mark a profound shift in the future regulatory landscape. This is due, in large part, to the fact that these therapies may treat certain diseases in a single dose.1

But the question becomes, how should genome editing medicinal products (GEMPs) be regulated?

Recent Casgevy Approval

The recent Casgevy approval marked a unique evaluation for the EMA and other national regulatory authorities, because of its novel concept and development. The European Medicines Agency (EMA) granted a conditional marketing approval (CMA) for Casgevy (exagamglogene autotemcel) to treat Beta thalassaemia requiring transfusions and sickle cell disease, using CRISPR-Cas9 technology.2 Read our executive summary of the Casgevy approval for more information.

Discussions on the ethics surrounding GEMPs have been ongoing for several years with numerous GEMP products currently in development. However, the Casgevy approval could signal the start of GEMPs being approved for different illnesses sooner than we think.

Therefore, this blog aims to highlight the implications of GEMPs from a social, ethical and regulatory viewpoint.

World Health Organisation’s response

The World Health Organization (WHO) formed the Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing. It was tasked with:3

  1. reviewing existing literature on human genome-editing research,
  2. considering existing governance proposals and initiatives, and
  3. creating the International Clinical Trials Registry.

In 2019 the WHO approved a global registry to keep abreast of human genome editing and called on researchers to register their somatic and germline clinical trials.

The WHO also developed a governance framework for human genome editing in 2021 which consists of 6 parts:

Part 1

Includes policy reports; scientific and technical aspects, past bioethical analyses of human genome editing, and identifies current, potential, and speculative human genome editing research.

Part 2

Explains ongoing value-based and principal-driven governance, including rules of the processes to manage public affairs and ensure transparency, participation, inclusivity and responsiveness.

Part 3

Identifies the values and principles that good governance is based on. Openness, transparency, honesty and accountability;  responsible regulatory stewardship; responsible stewardship of science and responsible stewardship of research resources.3

Part 3 of the framework includes 5 specific challenges to help adjust the oversight measures:3

  1. postnatal somatic human genome editing,
  2. prenatal (in utero) somatic human genome editing,
  3. heritable human genome editing,
  4. human epigenetic editing, and
  5. enhancement.

Part 4

This relates to who may need to be involved in the governance of genome editing (law, regulators, public advisory, professional bodies, etc).

Part 5

Includes seven scenarios to demonstrate how different parts of the governance framework come together practically. They are used to highlight the future challenges of governance concerning human genome editing research.

Part 6

Highlights several considerations for successfully implementing governance in human genome editing research. It also includes things the WHO and other organisations can do to strengthen governance.

The EMA’s perspective on genome-editing medicines

In 2020, a horizons paper from Hines et al discussed the potential regulatory implications for GEMPS utilising zinc finger nucleases, transcription activator-like effector nucleases (TALENs), CRISPR–Cas9 editors and prime editors.1

Hines et al discussed the hopeful potential for GEMPs to target rare diseases, particularly in instances where several mutations target a similar phenotype. They even noted the potential for GEMPs to become patient-specific, using these novel therapies to edit according to an individual’s genotype.1 However, several developmental considerations are necessary to get to this point due to several factors unique to GEMPs.

GEMP delivery

Delivery systems include plasmids, viral vectors, electroporation and nanoparticles1 among others, and each has variable efficacy, safety in vitro/in-vivo, and cell-targeting in vivo. This means that further research, particularly regarding immunogenicity is required in vivo to ensure delivery systems are adequate for clinical use.


The biggest consideration regarding non-clinical aspects of genome editing is on and off-target effects. The correct application of correctly identifying on and off-target effects and associated toxicities in humans is integral.

However, many factors affect on and off-target effects, including the genome-editing tool itself; its delivery system; the DNA target; the chromatin structure; the cell type and differentiation stage, and the duration of nuclease exposure.1 Different methods should be applied to ensure on and off-target effects are studied before use in a clinical setting.


Clinical considerations go hand in hand with ethical considerations for genome editing technologies. From a safety perspective, Hines et al recommend long-term registry studies as a way to measure the effects of genome editing technologies as they progress. Additionally, ethical considerations must be discussed concerning editing germline genome editing as this will have cascading implications for future generations.1 As the current genome editing technologies mainly focus on rare diseases, determining the most appropriate clinical trial design is important as the sample sizes are small and comparator and control arms are not feasible.

A more recent EMA perspective on genome-editing technologies

A more recent paper from Tavridou et al., 2024, summarised the insights the EMA has gained so far from 16 Scientific Advice procedures conducted with companies developing CRISPR products and other genome-editing medicinal products (GEMPs) between 2019 and 2022.4

Tavridou et al. recognised that there is limited scientific guidance available to encapsulate GEMP development. However, regulatory authorities are learning from the recent Casgevy approval and numerous GEMP products currently in development, to gain insights into how these novel therapies will shape future regulatory frameworks.

The majority of companies requesting SA for GEMPs were big pharma, and most companies sought SA in the preclinical or early clinical stages of development. The paper separated the lessons learned from SA proceedings on GEMP products into three developmental sections: quality, non-clinical and clinical.

Quality insights

The most frequent quality developmental challenges observed included:4

  • Characterisation and control,
  • designation of starting materials,
  • active substance definition,
  • excipients and impurities,
  • potency testing, and
  • comparability.

Tavridou et al recommended the questions and answers on the principles of GMP for the manufacturing of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs to help developers define starting materials, active substances and excipients of GEMPs.4 They also considered the active substance of GEMPs to be the genome editing

tools administered in vivo or the ex vivo modified cells. Additionally, carriers of genome editing tools were categorised as the excipients of GEMPs, and GEMP developers should review the committee for medicinal products for human use’s (CHMP’s) guideline on excipients for further information. 

Non-clinical insights

Reiterating the concerns of the Hines et al review, Tavridou et al considered off-target toxicity the predominant risk with CRISPR and other GEMPs as there are currently no analytical methods to assess potential genome editing errors. As such, the final product’s dose, mode and treatment schedules in non-clinical studies should reflect the intended use in clinical studies to identify off-target toxicities and outline its safe use in humans. Other important non-clinical considerations identified in SA procedures included:4

  • Off-target assessment strategy,
  • animal model selection,
  • biodistribution assessment, and
  • developmental and reproductive toxicity studies.

Tavridou et al., also recommended the guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials to inform how to choose the most relevant animal models to predict the clinical effects of GEMPs.

Clinical insights

Again, the main feature of clinical challenges observed in GEMP development related to the orphan nature of the diseases they were being developed for. This presented challenges in determining the best clinical trial designs for first-in-human or pivotal trials. Therefore, heterogeneity of patients included in clinical trials was a topic of discussion in several SA procedures. Other clinical trial considerations included:4

  • Dose selection,
  • time intervals between treatments,
  • population,
  • comparator,
  • endpoints,
  • sample size and statistical methods, and
  • safety and efficacy follow-up.

The EMA recommended that long-term follow-up trials for patients treated with CRIPSR and GEMPs be at least 15 years.4 In addition, specific post-authorisation measures should be discussed with regulatory authorities to properly measure the safety and efficacy of GEMPs. However, Tavridou et al., noted that the clinical SA offered to medicine developers of GEMPs was similar to the clinical advice offered to other ATMPs.

Overall, Tavridou et al., expressed the need for GEMP developers to seek SA early in development as the quality and non-clinical aspects of the development are closely associated with these novel medicines’ clinical safety and efficacy.


Genome editing is taking off. The first approval of Casgevy as a CRISPR-Cas9 technology marks a profound shift in the future of medicine development, but the question remains: is the regulation ready?

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Nicole Brooks, Regulatory Consultant / Copywriter


  1. Hines PA, Agricola E, Llinares Garcia J, O’Dwyer L, Herold R. (2022). Therapeutic genome editing: regulatory horizons. Nat Rev Drug Discov; 21(1):1–2. Available from:
  2. European Medicines Agency (2024). Casgevy Assessment Report. EMA/6332/2024 Committee for Medicinal Products for Human Use (CHMP). Procedure number: EMEA/H/C/005763/0000. Available from:
  3. WHO Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing. Human genome editing: a framework for governance. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO. Available from:
  4. Tavridou A, Rogers D, Farinelli G, Gravanis I, Jekerle V. (2024). Genome-editing medicinal products: the EMA perspective. Nat Rev Drug Discov. 23(4):242–3. Available from: